痰瘀同治优化方调节cGAS/STING信号通路抑制炎症改善心肌缺血再灌注无复流OA

Objective:This paper aims to investigate the protective effects of the Tanyu Tongzhi Youhua prescription(TYTZP)against myocardial ischemia/reperfusion injury in rats via regulation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)signaling pathway.Methods:Fifty-six 8-week-old male Sprague-Dawley(SD)rats were randomly divided into sham group,model group,ticagrelor group(32.4 mg·kg-1),RU320521(RU.521cGAS inhibitors)group(5 mL·kg-1),groups of TYTZP with low dose(3.6 g·kg-1),medium dose(7.2 g·kg-1),and high dose(14.4 g·kg-1),with eight rats per group.The ticagrelor group and groups of TYTZP with different doses received pre-treatment for seven days according to their respective protocols.The RU.521 group received an intraperitoneal injection one hour before modeling.A rat model of the no-reflow phenomenon in myocardial ischemia/reperfusion injury was established by ligating the left anterior descending coronary artery in situ.Myocardial no-reflow area was determined by thioflavin staining.Histopathological morphology of myocardial tissue was observed via hematoxylin and eosin(HE)staining.Cardiac function was detected by echocardiography.Myocardial microcirculation function change was observed by using real-time myocardial contrast echocardiography.The myocardial enzyme levels in the serum were measured by serum biochemical analysis.The double-stranded DNA(dsDNA)levels were detected by using PicoGreen.The protein expression of cGAS,STING,and nuclear factor-κB(NF-κB)p65 in myocardial tissue was detected by Western blot.The levels of cardiac troponin I(cTN I),cardiac troponin T(cTNT),interleukin-6(IL-6),interleukin-1β(IL-1β),and tumor necrosis factor-α(TNF-α)in the peripheral blood were measured by enzyme-linked immunosorbent assay(ELISA).Results:Compared with the sham group,the model group showed a significantly increased myocardial no-reflow area(P＜0.01).Myocardial fiber rupture and disarray and inflammatory cell infiltration were observed by HE staining.The ultrasound results indicated that left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS)(P＜0.01)were significantly decreased.Real-time myocardial contrast echocardiography showed that the peak time of myocardial blood perfusion was significantly prolonged(P＜0.01),and the levels of creatine kinase(CK),creatine kinase isoenzyme(CK-MB),lactate dehydrogenase(LDH),cTN I,cTNT,and dsDNA were significantly elevated(P＜0.01).Western blot results showed that the myocardial protein expressions of cGAS,STING,and NF-κB p65 were upregulated(P＜0.01).ELISA results showed that the inflammatory factors in the serum such as IL-6,IL-1β,and TNF-α were increased(P＜0.01).Compared with the model group,the group of the TYTZP significantly reduced the levels of myocardial enzyme,troponins,and dsDNA(P＜0.01,P＜0.05),improved cardiac function and myocardial microcirculation,alleviated histopathological morphology and inflammatory infiltration,inhibited activation of the cGAS/STING pathway,reduced the expression of NF-κB p65(P＜0.01,P＜0.05),and inhibited inflammatory response.Conclusion:The TYTZP mitigates the no-reflow phenomenon in myocardial ischemia/reperfusion injury,and its mechanism is associated with inhibiting the activation of the cGAS/STING pathway and attenuating inflammatory responses.